An analysis of T cell receptor (TCR) expression in Mlsc reactive T cells demonstrated a striking association of this reactivity with expression of the Vbeta3 gene product. In addition, it was demonstrated that mouse strains which express Mlsc delete expression of Vbeta3 in their mature peripheral T cell populations. This failure to express Vbeta3 presumably reflects a consequence of the maintenance of tolerance to self Mlsc products. These findings provide a basis for the understanding of high T cell precursor frequency for Mlsc products, reflecting the overall expression of Vbeta3 in the T cell repertoire. Moreover, they demonstrate the importance of these products in selection of the antigen-specific T cell repertoire. The range of self antigens that influence Vbeta usage was evaluated by studying the expression of 16 Vbeta families in inbred mouse strains. Significant decreases in expression occurred in 8 of the 16 Vbeta families. The self ligands responsible for these deletions appeared to consist of both MHC encoded and non-MHC encoded components. These results demonstrate that strain specific decrease in VA expression occur in a major portion of the T cell repertoire and that a number of self-MHC and non-MHC products induced these deletions in the process of eliminating self reactivate T cells from the mature T cell pool. Studies employing athymic nude mice demonstrated that Vbeta deletions associated with self tolerance failed to occur in athymic mice, demonstrating that the thymus has a critical mediating self tolerance by negative selection.